One of the major causes for death of cancer patients is metastasis of cancer, and it is also the reason why chemotherapies or immunotherapies currently in clinical use cannot greatly contribute to an increase in the viability of cancer patients.
Most solid tumor metastases show that cancer cells proliferate at the site where cancer cells first appear, and as the cancer mass grows larger, the tumor is provided with nutrition and oxygen needed for growth and proliferation via new blood vessels. Then, the cancer cells are separated from the cancer mass, migrate to other parts of the body through the blood vessels, and then settle in secondary sites, where cell proliferation again occurs. That is, the new blood vessels that penetrate into the tumor give metastatic cancer cells the opportunity to enter the blood circulation system, which is a crucial help for cancer cells to metastasize (Non-patent Document 1).
Signaling molecules that play a key role in growth and metastasis of cancers as well as angiogenesis are growth factors including VEGF (vascular endothelial growth factor) and receptors thereof. Receptor tyrosine kinase (RTK), which is a key part of growth factor receptors, is involved in various cell activities such as cell survival, differentiation, migration, proliferation and the like. Such RTK plays a key role in the growth and malignant process of cancers by abnormal regulation and overactivation in various cancer cells. Various kinds of RTK, including VEGF receptor 2 (KDR) tyrosine kinase, regulate survival and proliferation of cancer cells, and also induce angiogenesis by facilitating proliferation and migration of vascular endothelial cells, and tubular formation. In the case of cancers, various kinds of growth factors in addition to VEGF are secreted to stimulate RTK of cancer cells and vascular endothelial cells, thereby resulting in growth of tumors and metastasis via blood vessels. As such, in the case of inhibiting KDR tyrosine kinase only, cancer cells show resistance thereon, and growth of inhibited cancer is resumed. Therefore, inhibition of receptor RTK for various kinds of growth factors is an efficient strategy for developing anticancer drugs. The representative example is sunitinib (trademark: Sutent [sunitinib malate]), which is a multi-targeted RTK inhibitor.
In order for cancer cells to migrate into other parts of the body via blood vessels, cancer cells must go through an invasion process. For this, cancer cells secrete over-expressed proteinases to degrade the extracellular matrix. Such degradation enzymes include matrix metalloproteinases (MMPs), cathepsins and various proteinases. There are many types of MMPs, and MMPs are one of the most important enzyme groups that mediate invasion and metastasis of cancers by secreting from cells such as fibroblasts and macrophages in surrounding tissues of cancers, as well as cancer cells. Intercellular signaling by binding of VEGF to VEGFR2 inhibits the expression of MMP (Non-patent Document 2). In addition, MMP is involved in regulating the expression of VEGF or VEGFR2 (Non-patent Documents 3 and 4).
Integrated regulation of cancer growth, angiogenesis and metastasis would ultimately be an efficient way for treating cancer and decreasing the death rate due to metastasis of cancer. In addition, it would be efficient to select targeted molecules such as RTK which is involved in the overall processes of cancer growth, angiogenesis and cancer cell invasion/metastasis. Furthermore, the matter—that conventional anticancer drugs inhibiting cancer growth cause a toxicity problem due to long-term administration—requires the development of drugs that are efficient anticancer agents having inhibitory effect against metastasis and low toxicity.